The thyroid follicle is part of the endocrine circuitry regulating both oxidative metabolism and development of the nervous system. Hormone synthesis involves the integration of two crucial steps: uptake of iodide, and the transport of thyroglobulin (Tg) to the follicle lumen where it is iodinated to form thyroid hormone (9). For Tg as for many other secretory and plasma membrane proteins, export from the endoplasmic reticulum (ER) to the Golgi complex is rate-limiting in the overall process of intracellular transport. Moreover, only properly- folded Tg is competent for ER export or for thyroid hormone synthesis. Historically, there have been numerous reports of congenital goiter with abnormal Tg in which presumed defects within the primary structure lead to disturbed Tg export from the ER and severe hypothyroidism. More recent molecular studies support the contention that most cases of thyroid dyshormonogenesis are caused by defects in protein export from the ER. Since Tg enters the ER in a completely unfolded state, it must convert its raw primary structure into a tertiary/quatemary structure that is competent for transport. Unfolded Tg has exposed peptide regions that appear to signal interaction with a family of "molecular chaperone" proteins that are permanent residents of the ER: gradual folding of the nascent polypeptide buries these regions and progressively decreases the interactions with chaperones. By binding only to incompletely-fold Tg and not to the final, dimeric, - 660kD glycoprotein ER chaperones perform a quality control function limiting the export of malfolded molecules. How Tg is normally assembled into a bioactive form and transported from the ER, and the precise molecular defect in the folding and transport of Tg in a mouse model of congenital hypothyroidism, is the focus of the research proposal. It has recently been recognized that an increasing number of autosomal recessive diseases of childhood are caused b minor changes in polypeptide primary structure, suggesting that proper conformation of exportable proteins is critical for their transport as well as function. Thus, congenital hypothyroidism with defective Tg transport must be considered within a broader group of inborn errors of metabolism, which are now termed endoplasmic reticulum storage diseases (ERSD).